Despite several recent studies that have emphasized the importance of the kidney in regulating insulin homeostasis, our overall knowledge of renal insulin metabolism is incomplete. In particular, there is a large deficit in our understanding of the factors which determine the uptake of insulin by the luminal and contraluminal aspects of renal tubular cells both in health and disease. In order to further our understanding of the physiology of renal insulin metabolism, we will study the determinants of luminal and contraluminal insulin uptake in the isolated perfused rat kidney. This model permits the study of processes that would be difficult or impossible to study in the intact animal. Knowledge gained regarding normal physiology will form the basis of a study of renal insulin metabolism in diabetic ketoacidosis (DKA); a condition associated with abnormal insulin handling by the kidney. In this study we propose to examine firstly, the effects of spontaneous DKA on insulin metabolism in intact ("BB") Wistar rats and secondly, the individual effects of the major metabolic disturbances associated with DKA on insulin metabolism in the isolated rat kidney. Information derived from this study should provide a better understanding of the pathophysiology of renal insulin metabolism in DKA and thus help place the insulin therapy of DKA on a more rational basis.